α-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure

The two disulfide bonds of α-conotoxin ImI, a peptide antagonist of the α7 nicotinic acetylcholine receptor (nAChR), were systematically replaced with isosteric redox-stable cystathionine thioethers. Regioselective thioether formation was accomplished on solid support through substitution of a γ-chlorohomoalanine by an intramolecular cysteine thiol to produce hybrid thioether/ disulfide analogues (2 and 3) as well as a dual cystathionine analogue (4) that were found to be structurally homologous to α-conotoxin ImI by 1HNMR. The antagonistic activity at the α7 nAChR of cystathionine analogue 3 (pIC50 = 6.41 ( 0.09) was identical to that of α-conotoxin ImI (1, pIC50 = 6.41 ( 0.09), whereas those of 2 (pIC50 = 5.96 ( 0.09) and 4 (pIC50 = 5.89 ( 0.09) showed a modest decrease. The effect of oxidation of the thioethers to sulfoxides was also investigated, with significant changes in the biological activities observed ranging from a >30-fold reduction (2SdO) to a 3-fold increase (3SdOB) in potencies